Many compounds such as insecticides, plasticizers, and detergents can be classified as environmental estrogens or endocrine disrupters. At least some of these compounds are capable of binding to estrogen receptors (ERs) as ligands and therefore may affect gene regulation in estrogenic pathways. Exposure to these chemicals in the environment, in the food chain, and through occupational exposures, may affect human health and, through potential developmental effects in utero and increases in birth defects, the health of future generations. In addition, chemical compounds from soy and other plants have been identified that also have the potential to act as mimics of the natural female steroid hormone, estradiol, and these "phytoestrogens" have received attention as being beneficial to human health. Yet these compounds, since they also are capable of acting as estrogens, might also cause problems by interfering with the body's own natural hormonal regulation. These two classes of non-steroidal chemicals, both with the ability to act as estrogens, raise important questions. Mammals seem to be exposed to many potentially estrogenic signals. Why does it appear that only some of these signals disrupt endocrine signaling? Furthermore, the exposure to these compounds through soy and other foods is not a new phenomenon. If these compounds really interfere with hormonal signaling, why wouldn't there be more obvious detrimental effects on reproduction or development rather than apparent health benefits? This proposal is based on the idea that there are cellular compensatory adaptations to the presence of some of these estrogenic compounds, so that regulation by ERs can distinguish between valid natural signals and these non-steroidal mimics. We propose that this adaptation occurs through modulation of the expression of specific nuclear accessory proteins, the nuclear receptor coactivators and corepressors, by these compounds and even by estradiol. These adaptations would limit the actions of non-steroidal hormone mimics.